CZ2002186A3 - Process for preparing substituted benzothiazole compounds - Google Patents

Abstract

A single-step process for the preparation of formula (I) benzisothiazoles from 2-acylphenylthiocyanates. Formula (I) benzisothiazoles are useful as key intermediates in the manufacture of herbicidally active compounds.

Description

Technical field

The present invention relates to herbicidal agents and in particular to a process for the preparation of substituted benzothiazole compounds.

BACKGROUND OF THE INVENTION

Substituted-benzisothiazole herbicidal agents are, among other publications, described in U.S. Pat. No. 5484763 and WO 99/14216 and are desirable components of good pesticide programs with high crop selectivity. Said substituted benzisothiazole herbicidal agents are prepared from benzisothiazole and heteroarylisothiazole compounds.

Methods for preparing the benzisothiazole and heteroarylisothiazole compounds (isothiazoles) are described in the literature. However, the only known preparation process, which consists of one step, requires rough reaction conditions and allows a maximum yield of product of only 38%. This low yield significantly decreases when the heteroarylisothiazole ring is substituted (Canadian Journal of Chemistry, 1973, 51, 1741). These yields and reaction conditions are not applicable to large-scale production or industrial conditions.

The synthesis of said isothiazoles, which consists of two steps, requires the isolation of intermediates, resulting in an unwanted environmental burden by solvent waste. In addition, these preparation processes, which require harsh reaction conditions, use expensive reagents? and lead only to acceptable overall yields even for unsubstituted isothiazoles. (Journal of

Research, Synop., 1979, 395 and the Journal of the Chemical

Society, Perkin II, 1977, 1114.) partially relative

Chemical The present invention relates to substituted

In contrast, a one-step process for preparing the benzisothiazole compounds is useful for large-scale preparation.

The present invention further relates to compositions for obtaining a substituted benzisothiazole compound in good yield under relatively mild reaction conditions from readily available starting materials and reagents.

The present invention further relates to obtaining an environmentally friendly commercial source of substituted benzisothiazole intermediates for the preparation of important substituted benzisothiazole herbicidal agents.

• 4 • 4

4444 444 • 44 44 44 ·· ·· ·· 4444

SUMMARY OF THE INVENTION

The present invention relates to a process for preparing a benzisothiazole compound of formula I

wherein Y represents a hydrogen atom or a halogen atom;

R is CO ₂ R ₃ , C 1 -C ₆ alkyl optionally substituted with one or more halogen atoms, C 1 -C ₆ alkoxy, CO ₂ R 1 or COR ₂ groups, or a six membered heteroeyl ring optionally substituted with one or more halogen atoms, CN, NO ₂ , C 1 -C ₆ alkyl, C ₁ -C ₆ haloalkyl, C 1 -C ₆ alkoxy or C 1 - 6

C 7 haloalkoxy groups; and

R _HR R ₂ and R ₃ are each independently hydrogen, CxCgalkyl or NH ₂ wherein the method of preparation consists of reaction of compound II • · ··

wherein Y and R are as defined above with an ammonia source in the presence of a solvent.

The present invention also relates to a method of using a compound of formula I for the preparation of herbicidally active substituted benzisothiazole reagents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a one-step process for preparing a substituted benzisothiazole compound from the corresponding 2-acylphenylthiocyanate precursor. Said benzisothiazole compounds are useful as key intermediates in the preparation of important herbicidal agents such as those described in U.S. Pat. No. 5,484,763 and WO 99/14216. Such herbicidal agents are critical to the production and quality of the overall food supply. The efficient preparation of such herbicidally active compounds in an environmentally friendly manner presents a constant challenge.

The preparation process of the present invention provides a one-step preparation of a substituted benzisothiazole compound of formula I, wherein formula I is as defined above, from readily available starting materials and under relatively mild reaction conditions that allow efficient commercial scale production. Compounds of formula I that are preferably prepared by the process of the present invention are those wherein R is C 1 -C 8 alkyl or CO 2 R 3 and R 3 is C 1 -C 8 alkyl. More preferred compounds of formula I are those wherein Y is hydrogen or F and R is C 1 -C ₆ alkyl or CO 2 R 3.

The term halogen as used in the specification and claims refers to a chlorine atom, a fluorine atom, a bromine atom or an iodine atom. The term haloalkyl refers to an alkyl group, C _n H 2n + 1, which contains from one halogen atom to 2n + 1 halogen atoms. The term six-membered heterocyclic ring refers to a six-membered aromatic ring system containing one or two heteroatoms selected from the group consisting of O, N or S atoms and linked through a carbon atom. Examples of the six-membered heterocyclic ring include: pyridine, pyrimidine, pyran, thiopyran and the like.

In accordance with the process of the present invention, a benzisothiazole of the formula I can be conveniently prepared by reaction with a 2-acylphenylthiocyanate of the formula II which is appropriately substituted with an ammonia source such as ammonia, ammonium hydroxide, an ammonium salt such as ammonium chloride, ammonium acetate , ammonium trifluoroacetate and the like or any of the usual means;

- β • · * ♦ • · · which are the sources of the benefit of the polar flowchart above.

ammonia in the presence of a solvent, with a solvent. The reaction is shown in FIG

I, where Y and R are as defined above

Flowchart I

The compound of formula (II) can be readily prepared by conventional procedures such as the reaction of sodium thiocyanate with a benzoyl compound of formula (III), which is correspondingly substituted, in the presence of bromine and acid, of Chart II.

The reaction is shown in the developmental

Flowchart II

(II) (II)

Solvents suitable for use in the process of the present invention include polar solvents such as water, alcohols, organic acids, esters, and aprotic solvents such as dioxane or acetonitrile. Preferred solvents are water, dioxane or lower alkyl alcohols such as methanol, ethanol, propanol, isopropanol and the like or a mixture thereof.

The ammonia source may be any of the usual means for introducing ammonia, such as ammonia gas, ammonium hydroxide, ammonium salts and the like, preferably ammonium hydroxide or an ammonium salt. The ammonium salts which are useful in the process of the present invention are those which have sufficient solubility in the solvent to be used. Examples of suitable ammonium salts include trifluoroacetate, acetate, nitrate, sulfamate, chloride, sulfate and the like, preferably acetate or trifluoroacetate.

In the process of the present invention, the reaction temperature is directly related to the reaction rate, elevated temperatures result in increased reaction rates. However, too high temperatures can lead to unwanted side reactions and reduced yield and reduced product purity. A suitable reaction temperature range may range from near room temperature to the reflux temperature of the solvent used.

According to the state of the art, the acylphenylthiocyanate compound of formula II is treated with an ammonia source, preferably an ammonium hydroxide or an ammonium salt, in the presence of a solvent, preferably a polar solvent, more preferably water, dioxane or a low alkyl alcohol such as C 1 -C ₄ an alkyl alcohol, for example methanol or isopropanol or mixtures thereof, in a temperature range ranging from near room temperature to the reflux temperature of the solvent. When the reaction is complete, the desired benzisothiazole product of formula I is isolated using conventional procedures such as extraction, filtration, chromatography, and the like.

In the process of the present invention, the amount of ammonia source is not narrowly critical and amounts that are close to 1 to 5 molar equivalents, preferably amounts that are close to 1 to 3 molar equivalents can be used.

Obviously, a larger amount of ammonia source, i.e., greater than 5 molar equivalents, can be used, but this does not give any advantages.

The compounds of formula I are useful as intermediates in the manufacture of substituted benzisothiazole herbicidal agents. Accordingly, in one embodiment of the invention, a compound of formula I that is prepared from a compound of formula II as described above may be reacted with a cyclic compound of formula IVa or IVb.

(IVb) where

R ₄ and R ₅ are each independently hydrogen, C 1 -C ₆ alkyl, C 1 -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cyclohalogenalkyl or R ₄ and R ₅ together with the atoms to which they are attached to form a ring in which R ₄ R ₅ represents a five or six membered cycloalkylene group which may optionally be substituted by one to three halogen atoms or methyl groups;

R 8 and R ₇ are each independently hydrogen, halogen or C 1 -C ₆ haloalkyl;

R 5 and R 8 are each independently C 1 -C ₄ alkyl in the presence of an acid or a base, optionally in the presence of a solvent, to form a compound of formula V or a compound of formula IV wherein R ₁₀ is hydrogen;

and in the case of a compound of formula VI, optionally the compound of formula VI is further reacted with a C 1 -C ₆ alkyl halide, RuX, in the presence of a base to form a compound of formula VI wherein R ₁₀ is C 1 -C 4 alkyl. The reaction is shown in Flow Diagram III, wherein X is chloride or bromide.

Flowchart III

O

(VI) ^R 10 = C 1-6 alkyl

Among the known methods for converting a compound of formula I into herbicidally active products of formula V and formula VI are those described in U.S. Pat. patent number

5,484,763 and WO 99/14216.

DETAILED DESCRIPTION OF THE INVENTION

To illustrate the present invention, examples of the present invention are provided below. These examples are illustrative only and are not intended to limit the invention in any way.

NMR resonance a

Unless parts.

and HPLC represent nuclear magnetic high performance liquid chromatography. otherwise, parts are by weight

Example 1

Preparation of 2-acetyl-4-amino-5-fluorophenylthiocyanate

A 2M solution of bromine in acetic acid (32.7 mL, 65.4 mmol) was added dropwise to a stirred mixture of 4-acetyl-2-aminofluorobenzene (5.0 g, 32.6 mmol) and sodium thiocyanate (7.94 ϊ).

, Φ ·,,,, g, 97.9 mmol) in glacial acetic acid. The reaction mixture was stirred at room temperature for one hour, poured into water and extracted with ethyl acetate. The extracts were combined, followed by washing with water and brine, dried over magnesium sulfate, and concentrated in vacuo to give the title compound as an orange solid, 4.68 g, yield: 68% ¹ HNMR spectroscopy and HPLC analysis.

Example 2

Preparation of 5-amino-6-fluoro-3-methylbenzisothiazole

A solution of 2-acetyl-4-amino-5-fluorophenylthiocyanate (100 mg, 0.476 mmol) in methanol was treated with 30% ammonium hydroxide (4 mL) and stirred for 42 hours. The reaction mixture was poured into water and extracted with ethyl acetate. Combine the extracts, wash with brine, dry over magnesium sulfate, and concentrate in vacuo to an oil. The oil was subjected to chromatography (silica gel / hexane / ethyl acetate as eluent) to give the title product as an orange solid, 36.9 mg, 56% yield, determined by ¹ H NMR spectroscopy and HPLC analysis.

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Example 3

Preparation of 3-amino-4-fluoro-6-thiocyanatophenyl 2- (3-methylpyridyl) ketone

A solution of bromine in acetic acid (12 mL, 0.024 mol) was added dropwise to a stirred mixture of 3-amino-4-fluorophenyl 2- (3-methylpyridyl) ketone (4.20 g, 0.017 mol) and sodium thiocyanate (4.15 g). , 0.051 mol) in glacial acetic acid and stirred at room temperature for one hour. The reaction mixture was poured into cold aqueous ammonia solution and filtered. The filtrate was dried over calcium sulfate in a vacuum oven to give the title compound as a yellow solid, 4.19 g, 80% yield, determined by ^{Χ 13} , ¹³ C and ¹⁹ F NMR and mass spectral analyzes.

Example 4

Preparation of 5-amino-6-fluoro-3- (3-methyl-2-pyridyl) benzoisothiazole

A mixture of 3-amino-4-fluoro-6-thiocyanatophenyl 2- (3-methylpyridyl) ketone (2.74 g, 0.01 mol) and 30% ammonium hydroxide in methanol was stirred overnight at room temperature, diluted ten times with the same solution. amount of methanol and 30% ammonium hydroxide solution and filtered. The filtrate was dried to give the title compound as a yellow solid, 1.31 g, 51% yield, determined by ¹ H, ¹³ C and ¹⁹ F NMR and mass spectral analysis.

Example 5

Preparation of ethyl (5-amino-4-fluoro-2-thiocyanate-phenyl) glyoxylate

A solution of ethyl 5-amino-4-fluorophenyl) glyoxylate (90 g, 0.426 mol) and sodium thiocyanate (114 g, 1.41 mol) in acetic acid was treated dropwise with a 2M solution of bromine in acetic acid (980 mL, 0.98 mmol) and stirred for one hour. The reaction mixture was poured on ice and extracted with ethyl acetate. The extracts were combined, washed with water and brine, dried over magnesium sulfate and concentrated in vacuo to give an oily residue. Purify the residue by flash chromatography (silica gel / hexane-ethyl acetate as eluent) to give the title product as a yellow solid, 60 g, 52% yield, determined by ¹ HNMR analysis.

Example 6

Preparation of ethyl 5-amino-6-fluoro-1,2-benzisothiazole-3-carboxylate

A solution of ethyl (5-amino-4-fluoro-2-thiocyanatophenyl) glyoxylate (1.00 g, 3.73 mmol) in dioxane under nitrogen was treated with ammonium trifluoroacetate (1.71 g, 13 mmol) and heated The mixture was refluxed for 2 hours. The reaction mixture is subjected to chromatography (silica gel / ♦ 0)

Hexane-ethyl acetate as eluent) to give the title product as a light green solid, 0.59 g, 66% yield, determined by ¹ HNMR analysis.

Example 7

Preparation of 5-amino-3-substituted benzisothiazoles

Using essentially the same procedures described above and using the corresponding 2-acylphenylthiocyanate substrate, the compounds shown in Table I were obtained.

·

Table I

R Y Source ammonia Solvent Temperature melting point (° C) Yield (%) CH2OCH3 F NH ₄ O ₂ CCF ₃ Dioxane 88-90 37 2-pyridyl F nh ₄ oh Methanol 40 CH3CH2 F nh ₄ oh Dioxane

Represented by:

Dr. Otakar Švorčík

JUDr. Otakar Švorčík attorney

Halkova 2,120 00 Prague 2

Claims (15)

PATENT CLAIMS: A process for the preparation of a compound of formula I wherein Y represents a hydrogen atom or a halogen atom; R represents CO ₂ R ₃ , C 1 -C ₆ alkyl optionally substituted with one or more halogen atoms, C 1 -C ₆ alkoxy, CO ₂ R 1 or COR ₂ groups, or a six membered heterocyclic ring optionally substituted with one or more halogen atoms, CN groups , NO ₂ , C 1 -C 6 alkyl, C ₁ -C ₈ haloalkyl, C 1 -C 8 alkoxy or C ₂ -C ₆ haloalkoxy; and R 1, R ₂ and R 3 are each independently hydrogen, C ₁ -C ₆ alkyl or NH _2, wherein the process comprises reacting a compound of Formula II Wherein Y and R have an ammonia source as defined in the presence of a solvent. above The process according to claim 1, wherein the solvent comprises dioxane. The process of claim 1, wherein the solvent comprises water or a mixture thereof. characterized in that: C ₁ -C ₄ alkyl alcohol or A process according to claim 1 wherein the ammonia source is an ammonium hydroxide or an ammonium salt. 5. A process according to claim 4 wherein the ammonium salt is ammonium trifluoroacetate or ammonium acetate. A process for the preparation of a compound of the formula I according to claim 1, characterized in that Y represents a hydrogen atom or F. A process for the preparation of a compound of the formula I according to claim 1, characterized in that R represents C 1 -C 6 alkyl. • · * <0 0 · 9 9 9 9 9 0 * 0 0 9 9 8 Or CO 2 R 3 and R 3 represents C 1 -C ₄ alkyl. A process according to claim 5 wherein the solvent is selected from the group consisting of water, a C 1 -C ₄ alkyl alcohol, a mixture of water and a C 1 -C ₄ alkyl alcohol, and dioxane. A process for the preparation of a compound of formula I according to claim 8, characterized in that Y represents a hydrogen atom or F. A process for the preparation of a compound of formula I according to claim 9, characterized in that R represents C 1 -C ₆ alkyl or CO 2 R 3 and R 3 represents C 1 -C 4 alkyl. The method of claim 1, further comprising preparing a compound of Formula V or a compound of Formula VI (V) (VI) wherein Y is hydrogen or halogen; R represents CO 2 R 3, C 1 -C 6 alkyl optionally substituted by one or more halogen atoms, fcfc fcfcfcfcfcfcfcfcfc C 1 -C ₆ alkoxy, CO ₂ R 1 or COR ₂ or a six-membered heterocyclic ring optionally substituted with one or more halogen atoms, CN, NO ₂ , C 1 -C ₆ alkyl, C groups C ₂ haloalkyl, C 1 -C 6 alkoxy or C ₁ -C ₆ haloalkoxy; and R 1, R ₂ and R ₃ are each independently hydrogen, C ₁ -C ₆ alkyl or NH ₂ R 4 and R ₅ are each independently hydrogen, C ₁ -C ₆ alkyl, C 1 -C ₆ haloalkyl, C ₃ -C ₆ cycloalkyl, C ₃ -C ₆ cyclohalogenalkyl or R ₄ and R ₅ may together with the atoms to which they are attached to form a ring wherein R ₄ R ₅ represents a five or six membered cycloalkylene group, which may optionally be substituted by one to three halogen atoms or methyl groups; R 6 and R ₇ are each independently hydrogen, halogen or C 1 -C 6 haloalkyl; R 8 and R 8 are each independently C ₁ -C ₄ alkyl; and R 10 represents a hydrogen atom or a C 1 -C ₄ alkyl, by reacting a compound of formula I with a compound of formula IVa or IVb ♦ 4 * 4 4 <♦ * 4 4 4 »4 4 p R R O R R. O (IVa) (IVb) wherein R ₄ , R ₅ , R ₅ , R ₇ , R ₈ and R 8 are as defined above, in the presence of an acid or a base, optionally in the presence of a solvent, to form the desired compound of formula V or a compound of formula VI, wherein _R10 is hydrogen, or in the case of the formula VI compound reacting said compound with a C ₁ -C ₄ alkyl halide, RNX, wherein R _u represents a _Ci-C4 alkyl, and X represents chloride or bromide in the presence of a base to obtain a compound of formula VI wherein R ₁₀ is C 1 -C ₄ alkyl. A process according to claim 11 wherein the ammonia source is ammonium hydroxide, ammonium acetate or ammonium trifluoroacetate. 13. The process according to claim 11, characterized in that the solvent is dioxane, water, C ₁ -C ₄ alkyl alcohol or a mixture of water and _Ci-C4 alkyl alcohol. Process according to claim 11, characterized in that: Y represents F; R represents C 1 -C 6 alkyl or CO 2 R 3; R3 «· 494 ··· represents C ₁ -C ₄ alkyl; R ₆ and R ₇ are each independently hydrogen or CF ₃ ; and R _10a represents C 1 -C ₄ alkyl. Process according to Claim 14, characterized in that a compound of formula (VI) is prepared.